EP1346721A1 - Emulsion composite e/h/e - Google Patents

Emulsion composite e/h/e Download PDF

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Publication number
EP1346721A1
EP1346721A1 EP01998326A EP01998326A EP1346721A1 EP 1346721 A1 EP1346721 A1 EP 1346721A1 EP 01998326 A EP01998326 A EP 01998326A EP 01998326 A EP01998326 A EP 01998326A EP 1346721 A1 EP1346721 A1 EP 1346721A1
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EP
European Patent Office
Prior art keywords
type composite
water
composite emulsion
soluble
emulsion according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01998326A
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German (de)
English (en)
Other versions
EP1346721A4 (fr
Inventor
Tohru c/o TAISHO PHARMACEUTICAL CO LTD NAGAHAMA
Tomoaki c/o TAISHO PHARMACEUTICAL CO LTD YOSHINO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taisho Pharmaceutical Co Ltd filed Critical Taisho Pharmaceutical Co Ltd
Publication of EP1346721A1 publication Critical patent/EP1346721A1/fr
Publication of EP1346721A4 publication Critical patent/EP1346721A4/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/113—Multiple emulsions, e.g. oil-in-water-in-oil

Definitions

  • the present invention relates to a W/O/W type composite emulsion.
  • Liquid formulations are a type of formulation well adapted to use by ordinary people. For instance, liquid formulations for internal application can easily be administered to the aged people as well as to infants and children, who have low swallowing capability, so that liquid formulations are widely used as a medicine or a functional food.
  • the method of masking the unpleasant taste of a liquid formulation by blending various types of taste-improving agents in the liquid formulation is often employed.
  • this method of masking the unpleasant taste by blending taste-improving agents therein there are several restrictions such as the limited quantity of medical substances which can be blended in the liquid formulation.
  • W/O/W type composite emulsions are advantageous in that they permit blending of water-soluble medical medicines, which are generally not adapted to blending due to the stability and taste, in an internal aqueous phase. They are also advantageous in that they permit preparation of an administrative preparation in which such medical substances that easily react to each other and can hardly be blended together are incorporated in combination into a preparation, since the medical substances can be isolated from each other by including some of the medical substances in an internal aqueous phase and the others in an external aqueous phase.
  • W/O/W type composite emulsions are generally low in their stability, they are used in creamy preparations with high viscosity in which the stability is relatively preserved; however, there has been no report on use of W/O/W composite emulsions in such a preparation that is used as a liquid formulation for internal application with a viscosity of 150 mPa•s or below.
  • the utility value of the W/O/W type composite emulsion becomes higher as the quantity of medical substances which can be included in one particle of the emulsion is larger.
  • the percent inclusion of medical substances generally becomes lower.
  • the percent inclusion of medical substances into emulsion can be determined as satisfactory when a value (B/Log 10 C) obtained by dividing the percent inclusion (%) of medical substances included in the internal aqueous solution of the W/O/W type composite emulsion by a common logarithm of the average particle diameter of the W/O/W type composite emulsion is 27 or more.
  • a value (B/Log 10 C) obtained by dividing the percent inclusion (%) of medical substances included in the internal aqueous solution of the W/O/W type composite emulsion by a common logarithm of the average particle diameter of the W/O/W type composite emulsion is 27 or more.
  • JP 4-100536 A discloses, for instance,technique for production of W/O/W type composite emulsions by using polyglycerin-condensated ricinoleic acid ester, a lipophilic emulsifier.
  • the resulting emulsion cannot be satisfactorily applied to practical use, because it has an undesirably large particle diameter and undesirably low dispersion stability.
  • JP 4-99716 A describes a technique for producing an injection, but the injection produced by the technique cannot be used as a liquid formulation for internal application because of the unfavorable taste of the emulsifier.
  • W/O/W or S/O/W type emulsions are disclosed, for instance, in JP 3-127952 A, JP 10-158152 A, JP 10-203962 A, JP 11-188256 A, JP 11-240840 A, all the emulsions provided therein have an undesirably large particle diameter.
  • the inventors of the present invention made an extensive study with an objective to obtain a W/O/W type composite emulsion which has a sufficient stability even in the fine particle state and which can preserve the percent inclusion of medical substances included in the internal aqueous phase thereof at a high level.
  • the present invention provides a W/O/W type composite emulsion, wherein a W/O type emulsion comprising water, an oil ingredient and a lipophilic emulsifier each in a proportion expressed in term of mass ratio falling within a range enclosed with bold lines in Fig. 1 is dispersed in an external aqueous phase with a water-soluble macromolecule blended therein.
  • a W/O/W type composite emulsion with an average particle diameter in a range, within which the dispersing stability in a liquid formulation can be preserved easily, of 2000 nm or below by providing a W/O type emulsion produced as described above while incorporating water, an oil ingredient and a lipophilic emulsifier each in a specific proportion and dispersing the W/O type emulsion in an external aqueous phase with a water-soluble macromolecule, which W/O/W type composite emulsion can preserve the percent inclusion of the medical substances included in the internal aqueous phase at a high level.
  • the W/O/W type composite emulsion according to the present invention can make the volume of an internal aqueous phase larger, which enables in turn to drastically increase the quantity of medical substances included in each particle of the W/O/W type composite emulsion.
  • polyglycerin fatty acid ester having an HLB value of 10 or less is preferable.
  • the polymerization degree of the polyglycerin potion is preferably within the range of from 4 to 12.
  • the fatty acid portion of the polyglycerin fatty acid ester is an unsaturated fatty acid, more preferably, unsaturated fatty acid having 16 to 22 carbon atoms, and still more preferably, a hydroxy-unsaturated fatty acid.
  • oleic acid, linoleic acid, linolenic acid, ricinoleic acid and erucic acid are preferable and ricinoleic acid is particularly preferable.
  • Those especially preferable polyglycerin-condensed ricinoleic acid esters include tetraglycerin-condensed ricinoleic acid ester, hexaglycerin-condensed ricinoleic acid ester, pentaglycerin-condensed ricinoleic acid ester, decaglycerin-condensed ricinoleic acid ester and the like as well as the mixtures thereof.
  • Oil ingredients used in the present invention include commonly-used ones such as liquid paraffin, squalane, squalene, tocopherol, tocopherol acetate, tocopherol nicotinate, avocado oil, camellia oil, turtle oil, macadamia nuts oil, corn oil, mink oil, olive oil, rapeseed oil, yolk oil, sesame oil, wheat germ oil, Camellia sasanqua oil, castor oil, safflower oil, cottonseed oil, soybean oil, peanut oil and tricaprilyn, and of these tocopherol acetate is preferable.
  • fat-soluble medical substances may be blended in the oil ingredients.
  • the preferable water-soluble macromolecules used in the present invention include water-soluble proteins, water-soluble synthetic polymers, water-soluble polysaccharides and the derivatives thereof.
  • the water-soluble proteins include casein, sodium caseinate, ⁇ -lactoglobulin, ⁇ -lactalbumin, albumin, gelatin, soybean protein, and of these casein, sodium caseinate, ⁇ -lactoglobulin and ⁇ -lactalbumin are preferable.
  • the water-soluble synthetic polymers include polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, polyvinyl methyl ether and poly(sodium acrylate), and of these polyvinyl alcohol and polyvinyl pyrrolidone are preferable.
  • the water-soluble polysaccharides or the derivatives thereof include xanthan gum, gelan gum, dextran, pullulan, gum arabic, carrageenan, locust bean gum, dextrin, guar gum, pectin, sodium alginate, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose and carboxylmethylcellulose, and of these xanthan gum and hydroxypropylcellulose are preferable.
  • the water-soluble macromolecules can be used in combination of two or more.
  • the blend proportion of the water-soluble macromolecule according to the present invention preferably ranges from 0.001 to 20% by mass, and more preferably from 0.01 to 10% by mass, of the external aqueous phase.
  • the blend proportion of the water-soluble macromolecule is too small, it is difficult to produce a homogeneous and fine W/O/W type composite emulsion, while the blend proportion of the water-soluble macromolecule is too large, the resultant W/O/W type composite emulsion has an undesirably high viscosity for internal application.
  • the advantage of the present invention is fully exhibited, but even when commonly-used water-soluble medical substances are blended therein, the advantage can be expected inimprovement of the stability.
  • the blend proportion of the water-soluble macromolecule that can be blended in the internal aqueous phase varies depending upon the solubility, but the advantages of the present invention can be achieved by adjusting the blend proportions of the oil ingredient and lipophilic emulsifier taking into considerations the quantity of internal aqueous phase after the medical substances have been dissolved therein so as to meet the presently recited blend proportion of each of the components.
  • commercial value of the product can be improved by optionally blending pharmaceutical agents, other components, taste or odor reforming agents, pH adjusting agents, preservatives and the like in the external aqueous phase so far as the effect of the present invention is not adversely affected.
  • the W/O/W type composite emulsion according to the present invention can be produced as described below.
  • an oil phase such as an oil ingredient and lipophilic emulsifier is put into a container.
  • the container is set on an agitator such as a vacuum emulsifying machine.
  • the mixture is heated while agitating to a temperature in the approximate range of from 50 to 90°C, dissolved and homogenized.
  • the resultant mixture is added gradually a specified quantity of an aqueous phase containing substances and optional additives to be included in the internal aqueous phase, and the resultant mixture is emulsified while agitating the same at a constant temperature in the approximate range of from 50 to 90°C.
  • the resultant emulsion is cooled to 20 to 40°C while agitating for a certain period of time to obtain a W/O type emulsion.
  • the W/O type emulsion is formed so as to have an average particle diameter of from approximately 10 to 500 nm.
  • the W/O/W type composite emulsion can be produced by further dispersing this W/O type emulsion in an external aqueous phase containing a specified quantity of a water-soluble macromolecule and optional additives with any of the ordinary methods such as high-pressure homogenizer method, high-speed agitating method, ultrasonic wave emulsifying method and membrane emulsifying method. In addition, heating may be performed, if necessary, in the step of preparing the W/O/W type composite emulsion.
  • a Internal aqueous phase Ferric ammonium citrate 8.5 g Water 76.5 g b: Oil ingredient Tocopherol acetate 37.5 g c: Lipophilic emulsifier Polyglycerin-condensed ricinoleic acid ester (produced by Sakamoto Yakuhin Kogyo Co., Ltd., CRS-75) 127.5 g
  • Components b and c were heated to 70 to 80°C, and were homogeneously mixed and dissolved. Then the component a was gradually added to the resultant mixture while agitating. The mixture was agitated and emulsified while maintaining the liquid temperature at approximately 70 to 80°C. The resultant emulsion was further agitated for a certain period of time while gradually cooling it to a temperature of from 20 to 40°C to obtain a W/O type emulsion.
  • the average particle diameter of the W/O type emulsion determined with a grain size distribution measuring device based on dynamic light scattering system was 113.8 nm.
  • the W/O type emulsion obtained as described above was added, while agitating it with a homogenizer, to 180 g of an aqueous solution containing 0.5% by mass of sodium caseinate and 20% by mass of sugar, to obtain a W/O/W type composite emulsion with a relatively large particle diameter. Thereafter, the W/O/W type composite emulsion was passed through a perforated membrane to obtain a fine W/O/W type composite emulsion with an average particle diameter of 799.6 nm. The average particle diameter of the W/O/W type composite emulsion was determined with a grain size distribution measuring device based on laser beam diffraction/scattering system (HORIBA LA-920).
  • Percent inclusion (%) (Wi - Wo x A)/Wi x 100 wherein Wi is a mass of substances included in the W/O/W type composite emulsion; Wo is a mass of substances included in the external aqueous phase; and A is a quotient of the mass of external aqueous phase by the mass of W/O/W type composite emulsion ((mass of external aqueous phase)/(mass of W/O/W type composite emulsion)).
  • the mass of the substances included in the W/O/W type composite emulsion was measured after preprocessing by means of wet cineration method, etc., whereas the mass of the substances included in the external aqueous phase was measured after subjecting the W/O/W type composite emulsion to centrifugation to separate the particles of the W/O/W type composite emulsion from the external aqueous phase, each with atomic absorption method, respectively.
  • the percent inclusion of the included substances was 98.29%.
  • Example 1 Each of the samples was prepared with the composition shown in Table 1 in the same production method as that employed in Example 1. The average particle diameter of the W/O type emulsion was also measured in the same manner as that employed in Example 1.
  • FAC indicates ferric ammonium citrate
  • PGCR indicates polyglycerin-condensed ricinoleic acid ester (produced by Sakamoto Kogyo Co., Ltd., CRS-75).
  • the W/O/W type composite emulsion was prepared by the same production method as that employed in Example 1.
  • the average particle diameter of the W/O/W type composite emulsion was also measured in the same manner as that in Example 1.
  • the percent inclusion of the substances (In this case, the included substance was iron) in the W/O/W type composite emulsion was measured in the same manner as that in Example 1.
  • the W/O/W type composite emulsions were very fine as well as they met the requirement that the value obtained by dividing the percent inclusion (%) of the medical substances dissolved in the internal aqueous phase of the W/O/W type composite emulsion by the common logarithm for the average particle diameter of the W/O/W type composite emulsion (nm) (B/Log 10 C in Table 1) is 27 or more (See Examples 1 to 8).
  • Each of the samples was prepared with the composition shown in Table 2 or 3 by the same production method as that employed in Example 1.
  • the average particle diameter of the W/O type emulsion was also measured in the same manner as that employed in Example 1.
  • the percent inclusion of the included substances (the included substance was iron in the Examples herein) in the fine W/O/W type composite emulsion was measured in the same manner as that employed in Example 1.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Colloid Chemistry (AREA)
EP01998326A 2000-11-29 2001-11-29 Emulsion composite e/h/e Withdrawn EP1346721A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2000362918 2000-11-29
JP2000362918 2000-11-29
PCT/JP2001/010422 WO2002043698A1 (fr) 2000-11-29 2001-11-29 Emulsion composite e/h/e

Publications (2)

Publication Number Publication Date
EP1346721A1 true EP1346721A1 (fr) 2003-09-24
EP1346721A4 EP1346721A4 (fr) 2009-04-29

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EP01998326A Withdrawn EP1346721A4 (fr) 2000-11-29 2001-11-29 Emulsion composite e/h/e

Country Status (8)

Country Link
US (1) US6984691B2 (fr)
EP (1) EP1346721A4 (fr)
JP (1) JP3930805B2 (fr)
KR (1) KR20030059274A (fr)
CN (1) CN1482900A (fr)
AU (2) AU1849802A (fr)
CA (1) CA2430286A1 (fr)
WO (1) WO2002043698A1 (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101023860B1 (ko) 2005-10-14 2011-03-22 아지노모토 가부시키가이샤 Ｗ１/ｏ/ｗ２형 복합 유화 드레싱류 및 그의 제조 방법
EP1956920A1 (fr) * 2005-11-22 2008-08-20 Nestec S.A. Phase lipidique facilement dispersible
PL1957041T3 (pl) * 2005-11-22 2011-02-28 Nestec Sa Emulsja olej-w-wodzie i jej zastosowanie dla nadania funkcji
EP1954384A1 (fr) * 2005-11-23 2008-08-13 Nestec S.A. Emulsion huile dans eau utilisee pour creer de nouvelles consistances de produits
KR101655346B1 (ko) * 2009-11-27 2016-09-08 (주)아모레퍼시픽 고유상 안정화 화장료 조성물
JP6137305B2 (ja) * 2013-05-01 2017-05-31 キユーピー株式会社 複合乳化調味料
CN104642835A (zh) * 2013-11-19 2015-05-27 丰益(上海)生物技术研发中心有限公司 含有多不饱和脂肪酸源的组合物及其制备方法
CN108652001B (zh) * 2018-03-08 2021-07-20 江苏大学 一种矢车菊素-3-葡萄糖苷复乳的制备方法
WO2020111144A1 (fr) * 2018-11-29 2020-06-04 デンカ株式会社 Procédé de production de latex et latex
CN109645499A (zh) * 2018-12-27 2019-04-19 中国农业科学院农产品加工研究所 掩蔽食源性活性肽苦味的复合凝聚包埋系统的制备方法
CN110368322A (zh) * 2019-07-30 2019-10-25 浙江大学 同时包埋熊果苷和香豆酸的乳清蛋白果胶复合双乳液的制备方法及其产品
CN111631271A (zh) * 2020-05-22 2020-09-08 南昌大学 一种稳定w/o/w型多重乳液的制备方法
CN112210357B (zh) * 2020-10-23 2023-03-03 中国石油大学(华东) 一种w/o/w型多重乳状液堵水体系及其制备方法
CN112826009B (zh) * 2021-01-14 2022-08-12 苏州鲜活饮品股份有限公司 双重乳化水溶性色素乳液及其制备方法

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JPS60203139A (ja) * 1984-03-27 1985-10-14 Meiji Milk Prod Co Ltd 食品用ｗ／ｏ／ｗ型複合エマルジヨンの製造法
JPH11240840A (ja) * 1998-02-23 1999-09-07 Taiyo Kagaku Co Ltd アレルギー予防用組成物

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JPS60203139A (ja) * 1984-03-27 1985-10-14 Meiji Milk Prod Co Ltd 食品用ｗ／ｏ／ｗ型複合エマルジヨンの製造法
JPH11240840A (ja) * 1998-02-23 1999-09-07 Taiyo Kagaku Co Ltd アレルギー予防用組成物

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Title
See also references of WO0243698A1 *

Also Published As

Publication number Publication date
WO2002043698A1 (fr) 2002-06-06
KR20030059274A (ko) 2003-07-07
CN1482900A (zh) 2004-03-17
AU1849802A (en) 2002-06-11
US20040010078A1 (en) 2004-01-15
AU2002218498B2 (en) 2006-03-30
EP1346721A4 (fr) 2009-04-29
JP3930805B2 (ja) 2007-06-13
CA2430286A1 (fr) 2002-06-06
JPWO2002043698A1 (ja) 2004-04-02
US6984691B2 (en) 2006-01-10

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